Sweeteners Show a Plasticizing Effect on PVP K30-A Solution for the Hot-Melt Extrusion of Fixed-Dose Amorphous Curcumin-Hesperetin Solid Dispersions.

The co-administration of curcumin and hesperetin might be beneficial in terms of neuroprotective activity; therefore, in this study, we attempted to develop a fixed-dose formulation comprising these two compounds in an amorphous state. The aim of obtaining an amorphous state was to overcome the limitations of the low solubility of the active compounds. First, we assessed the possibility of using popular sweeteners (erythritol, xylitol, and sorbitol) as plasticizers to reduce the glass transition temperature of PVP K30 to prepare the polymer-excipient blends, which allowed the preparation of amorphous solid dispersions via hot-melt extrusion at a temperature below the original glass transition of PVP K30. Erythritol proved to be the superior plasticizer. Then, we focused on the development of fixed-dose amorphous solid dispersions of curcumin and hesperetin. Powder X-ray diffraction and thermal analysis confirmed the amorphous character of dispersions, whereas infrared spectroscopy helped to assess the presence of intermolecular interactions. The amorphous state of the produced dispersions was maintained for 6 months, as shown in a stability study. Pharmaceutical parameters such as dissolution rate, solubility, and in vitro permeability through artificial membranes were evaluated. The best improvement in these features was noted for the dispersion, which contained 15% of the total content of the active compounds with erythritol used as the plasticizer.

Clinical efficacy and tolerability of venetoclax plus rituximab in patients with relapsed or refractory chronic lymphocytic leukemia-a real-world analysis of the Polish Adult Leukemia Study Group.

The results of the MURANO trial showed encouraging progression-free survival (PFS) and overall survival (OS) in relapsed/refractory chronic lymphocytic leukemia (RR-CLL) patients treated with venetoclax-rituximab (VEN-R). A retrospective analysis was performed to evaluate the efficacy and safety of VEN-R within the Polish Adult Leukemia Study Group (PALG) centers. The study group included 117 patients with RR-CLL (with early relapse after immunochemotherapy or bearing TP53 aberrations) treated with VEN-R in 2019-2023 outside clinical trials. Patients were treated with a median of 2 (range 1-9) previous lines of therapy. Twenty-two participants were previously treated with BTKi (18.8% out of 117). The median follow-up was 20.3 months (range 0.27-39.1). The overall response rate (ORR) was 95.3% in the group of patients in whom a response to treatment was assessed and 86.3% for all patients. Twenty patients (17.1% out of 117) achieved a complete response (CR), 81 (69.2%) achieved a partial response (PR), and in 5 patients (4.3%), disease progression was noted (assessed as the best response during treatment). The median PFS in the whole cohort was 36.97 (95% CI 24.5, not reached) months, and the median OS was not reached (95% CI 27.03, not reached). Thirty-six patients died during the follow-up, 10 (8.5%; 27.8% of deaths) due to COVID-19 infection. All grade neutropenia (n = 87/117, 74.4%; grade 3 or higher n = 67/117, 57.3%) was the most common treatment adverse event. Forty-five patients (38.5%) remained on treatment, and twenty-two (18.8%) completed 24 months of therapy, while it was discontinued in fifty cases (42.7%). In this real-world setting of early access in very high-risk RR-CLL patients, the VEN-R regimen was associated with shorter median PFS compared with the results of the MURANO trial. This outcome, however, could be attributed to patients' exposure to SARS-CoV-2 infection and the aggressive course of the disease as very high-risk patients, after multiple lines of prior therapies, were included in the Polish Ministry of Health reimbursement program.

Hot-Melt Extrusion as an Effective Technique for Obtaining an Amorphous System of Curcumin and Piperine with Improved Properties Essential for Their Better Biological Activities.

Poor bioavailability hampers the use of curcumin and piperine as biologically active agents. It can be improved by enhancing the solubility as well as by using bioenhancers to inhibit metabolic transformation processes. Obtaining an amorphous system of curcumin and piperine can lead to the overcoming of these limitations. Hot-melt extrusion successfully produced their amorphous systems, as shown by XRPD and DSC analyses. Additionally, the presence of intermolecular interactions between the components of the systems was investigated using the FT-IR/ATR technique. The systems were able to produce a supersaturation state as well as improve the apparent solubilities of curcumin and piperine by 9496- and 161-fold, respectively. The permeabilities of curcumin in the GIT and BBB PAMPA models increased by 12578- and 3069-fold, respectively, whereas piperine's were raised by 343- and 164-fold, respectively. Improved solubility had a positive effect on both antioxidant and anti-butyrylcholinesterase activities. The best system suppressed 96.97 ± 1.32% of DPPH radicals, and butyrylcholinesterase activity was inhibited by 98.52 ± 0.87%. In conclusion, amorphization remarkably increased the dissolution rate, apparent solubility, permeability, and biological activities of curcumin and piperine.

Amorphous System of Hesperetin and Piperine-Improvement of Apparent Solubility, Permeability, and Biological Activities.

The low bioaccessibility of hesperetin and piperine hampers their application as therapeutic agents. Piperine has the ability to improve the bioavailability of many compounds when co-administered. The aim of this paper was to prepare and characterize the amorphous dispersions of hesperetin and piperine, which could help to improve solubility and boost the bioavailability of both plant-origin active compounds. The amorphous systems were successfully obtained by means of ball milling, as confirmed by XRPD and DSC studies. What's more, the FT-IR-ATR study was used to investigate the presence of intermolecular interactions between the systems' components. Amorphization enhanced the dissolution rate as a supersaturation state was reached, as well as improving the apparent solubility of both compounds by 245-fold and 183-fold, respectively, for hesperetin and piperine. In the in vitro permeability studies simulating gastrointestinal tract and blood-brain barrier permeabilities, these increased by 775-fold and 257-fold for hesperetin, whereas they were 68-fold and 66-fold for piperine in the GIT and BBB PAMPA models, respectively. Enhanced solubility had an advantageous impact on antioxidant as well as anti-butyrylcholinesterase activities-the best system inhibited 90.62 ± 0.58% of DPPH radicals and 87.57 ± 1.02% butyrylcholinesterase activity. To sum up, amorphization considerably improved the dissolution rate, apparent solubility, permeability, and biological activities of hesperetin and piperine.

Amorphous Solid Dispersion of Hesperidin with Polymer Excipients for Enhanced Apparent Solubility as a More Effective Approach to the Treatment of Civilization Diseases.

The present study reports amorphous solid dispersions (ASDs) of hesperidin (Hes) prepared by ball milling to improve its solubility and apparent solubility over the unmodified compound. The carriers were Soluplus® (Sol), alginate sodium (SA), and hydroxypropylmethylcellulose (HPMC). XRPD analysis confirmed full amorphization of all binary systems in 1:5 w/w ratio. One glass transition (Tg) observed in DSC thermograms of hesperidin:Soluplus® (Hes:Sol) and hesperidin:HPMC (Hes:HPMC) 1:5 w/w systems confirmed complete miscibility. The mathematical model (Gordon-Taylor equation) indicates that the obtained amorphous systems are characterized by weak interactions. The FT-IR results confirmed that hydrogen bonds are responsible for stabilizing the amorphous state of Hes. Stability studies indicate that the strength of these bonds is insufficient to maintain the amorphous state of Hes under stress conditions (25 °C and 60 °C 76.4% RH). HPLC analysis suggested that the absence of degradation products indicates safe hesperidin delivery systems. The solubility and apparent solubility were increased in all media (water, phosphate buffer pH 6.8 and HCl (0.1 N)) compared to the pure compound. Our study showed that all obtained ASDs are promising systems for Hes delivery, wherein Hes:Sol 1:5 w/w has the best solubility (about 300-fold in each media) and apparent solubility (about 70% in phosphate buffer pH 6.8 and 63% in HCl).

Bioavailability of Hesperidin and Its Aglycone Hesperetin-Compounds Found in Citrus Fruits as a Parameter Conditioning the Pro-Health Potential (Neuroprotective and Antidiabetic Activity)-Mini-Review.

Hesperidin and hesperetin are polyphenols that can be found predominantly in citrus fruits. They possess a variety of pharmacological properties such as neuroprotective and antidiabetic activity. However, the bioavailability of these compounds is limited due to low solubility and restricts their use as pro-healthy agents. This paper described the limitations resulting from the low bioavailability of the presented compounds and gathered the methods aiming at its improvement. Moreover, this work reviewed studies providing pieces of evidence for neuroprotective and antidiabetic properties of hesperidin and hesperetin as well as providing a detailed look into the significance of reported modes of action in chronic diseases. On account of a well-documented pro-healthy activity, it is important to look for ways to overcome the problem of poor bioavailability.

Amorphous Inclusion Complexes: Molecular Interactions of Hesperidin and Hesperetin with HP-Β-CD and Their Biological Effects.

This study aimed at obtaining hesperidin (Hed) and hesperetin (Het) systems with HP-ß-CD by means of the solvent evaporation method. The produced systems were identified using infrared spectroscopy (FT-IR), X-ray powder diffraction (XRPD), and differential scanning calorimetry (DSC). Moreover, in silico docking and molecular dynamics studies were performed to assess the most preferable site of interactions between tested compounds and HP-ß-CD. The changes of physicochemical properties (solubility, dissolution rate, and permeability) were determined chromatographically. The impact of modification on biological activity was tested in an antioxidant study as well as with regards to inhibition of enzymes important in pathogenesis of neurodegenerative diseases. The results indicated improvement in solubility over 1000 and 2000 times for Hed and Het, respectively. Permeability studies revealed that Hed has difficulties in crossing biological membranes, in contrast with Het, which can be considered to be well absorbed. The improved physicochemical properties influenced the biological activity in a positive manner by the increase in inhibitory activity on the DPPH radical and cholinoesterases. To conclude the use of HP-ß-CD as a carrier in the formation of an amorphous inclusion complex seems to be a promising approach to improve the biological activity and bioavailability of Hed and Het.

Low symptomatic COVID-19 in an elderly patient with follicular lymphoma treated with rituximab-based immunotherapy: A case report.

BACKGROUND: Follicular lymphoma is an indolent lymphoma that may progress to a highly aggressive form requiring immunochemotherapy. Most regimens utilize rituximab, an anti-CD20 monoclonal antibody, which may affect the clinical course of novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections [coronavirus disease 2019 (COVID-19)]. Here we describe the first case of mild COVID-19 during ongoing oncological treatment without significant deterioration after rituximab administration. CASE SUMMARY: A 74-year-old female with an enlargement of her right palatine tonsil was diagnosed with follicular lymphoma following tonsillectomy and started immunochemotherapy according to the rituximab, cyclophosphamide, vincristine, prednisone regimen. At home before the fourth cycle, she developed nonspecific symptoms (excessive fatigue, loss of appetite and nausea), misdiagnosed as adverse effects of chemotherapy. Unexpectedly, interim positron emission tomography-computed tomography scan, performed shortly before rituximab administration, revealed previously nonexistent pulmonary changes, potentially of infectious etiology. SARS-CoV-2 infection was confirmed by a nasopharyngeal swab (with reverse transcriptase polymerase chain reaction test) performed the following day. Despite rituximab infusion, the patient remained oligosymptomatic and was discharged home for self-isolation. Having reached a negative SARS-CoV-2 status before the subsequently scheduled regimen, the patient successfully received six cycles of rituximab, cyclophosphamide, vincristine, prednisone and obtained complete remission by positron emission tomography-computed tomography. CONCLUSION: Our case shows that rituximab-based immunotherapy due to follicular lymphoma may have no evident negative effect on the COVID-19 clinical course.

Analysis of the Composition of Lyophilisates Obtained from Aloe arborescens Gel of Leaves of Different Ages from Controlled Crops.

The aim of the study is to evaluate the composition of lyophilisates obtained from Aloe arborescens leaf gel at the age of one to four years. The leaves were obtained from controlled crops, which allowed to exclude environmental factors as variables. It was confirmed that the lyophilisates obtained from different years of Aloe arborescens leaf gel varied in chromatographic analyses in terms of aloin A and aloenin A content (high-performance liquid chromatography with diode-array detection HPLC-DAD, high-performance liquid chromatography with tandem mass spectrometric detection HPLC-MS/MS). Similarly, while testing the phenolic acids and the sum of polyphenols content, differences in their levels in leaf gel lyophilisates from plants of individual years were observed (spectrophotometric method UV-VIS). The lyophilisate composition analysis showed that the one-year-old leaves were characterized by the highest content of aloin A and aloenin A. While the content of polyphenols, including phenolic acids, was higher in the leaves of older plants. The antioxidant potential of the tested lyophilisates was assessed simultaneously. Regardless of the research model used (CUPRAC, DPPH, ABTS), an antioxidant effect was noted for Aloe arborescens leaves.

Combinations of Freeze-Dried Amorphous Vardenafil Hydrochloride with Saccharides as a Way to Enhance Dissolution Rate and Permeability.

To improve physicochemical properties of vardenafil hydrochloride (VAR), its amorphous form and combinations with excipients-hydroxypropyl methylcellulose (HPMC) and ß-cyclodextrin (ß-CD)-were prepared. The impact of the modification on physicochemical properties was estimated by comparing amorphous mixtures of VAR to their crystalline form. The amorphous form of VAR was obtained as a result of the freeze-drying process. Confirmation of the identity of the amorphous dispersion of VAR was obtained through the use of comprehensive analysis techniques-X-ray powder diffraction (PXRD) and differential scanning calorimetry (DSC), supported by FT-IR (Fourier-transform infrared spectroscopy) coupled with density functional theory (DFT) calculations. The amorphous mixtures of VAR increased its apparent solubility compared to the crystalline form. Moreover, a nearly 1.3-fold increase of amorphous VAR permeability through membranes simulating gastrointestinal epithelium as a consequence of the changes of apparent solubility (Papp crystalline VAR = 6.83 × 10-6 cm/s vs. Papp amorphous VAR = 8.75 × 10-6 cm/s) was observed, especially for its combinations with ß-CD in the ratio of 1:5-more than 1.5-fold increase (Papp amorphous VAR = 8.75 × 10-6 cm/s vs. Papp amorphous VAR:ß-CD 1:5 = 13.43 × 10-6 cm/s). The stability of the amorphous VAR was confirmed for 7 months. The HPMC and ß-CD are effective modifiers of its apparent solubility and permeation through membranes simulating gastrointestinal epithelium, suggesting a possibility of a stronger pharmacological effect.

Infectious complications during immunochemotherapy of post-transplantation lymphoproliferative disease-can we decrease the risk? Two case reports and review of literature.

BACKGROUND: Post-transplant lymphoproliferative disease (PTLD) is a heterogeneous group of diseases that develop after solid organ and hematopoietic stem cells transplantation related to intensive immunosuppression regimen, T-cell depletion and Epstein-Barr virus infection. Despite the improvement in the management of PTLD, the prognosis remains poor. Here we report the management of two transplanted patients with PTLD and infections during immunochemotherapy (ICTH). CASE SUMMARY: Of 65-year-old woman 11 years after kidney transplantation (first case) presented with diffuse large B-cell lymphoma (DLBCL) CS III and started ICHT according to R-CHOP protocol. Despite the secondary prevention of neutropenic fever, the patient developed grade 4 neutropenia with urinary and pulmonary tract infections after the fifth cycle. ICTH was continued in reduced doses up to 7 cycles followed by involved-field radiation therapy of the residual disease. The second case presents a 49-year-old man, 8 years after liver transplantation due to cirrhosis in the course of chronic hepatitis B, who started ICTH for DLBCL Burkitt-like CS IV. The patient received four cycles of ICTH according to R-CODOX/R-IVAC protocol, with reduced doses. In both cases initially undertaken reduction of immunosuppression was ineffective to prevent infectious complications. Despite one incomplete ICHT treatment due to recurrent infections, both our patients remain in complete remission. CONCLUSION: Reduction of immunosuppression and the doses of chemotherapeutics may be insufficient to prevent infectious complications during ICTH in PTLD patients.

Successful chemotherapy with liposomal doxorubicin for metastatic Kaposi's sarcoma without skin involvement in the kidney transplant recipient.

Kaposi's sarcoma (KS), one of the most typical malignancies after kidney transplantation, is strongly associated with human herpes virus 8 infection. More than 90% of patients had primary skin changes, which make the diagnosis easier and faster. The lack of skin lesions is considered rare, especially in the iatrogenic type of sarcoma, including patients on immunosuppression and may cause a diagnostic challenge due to the variety of organ involvement, imitating other diseases. The aim of this case presentation is to raise attention to the atypical clinical manifestation of this malignancy. Currently, several different therapeutic options are available for patients with KS, including reduction of immunosuppression, conversion of immunosuppression to mTOR inhibitors, or chemotherapy. Here, we present an unusual case of advanced KS human immunodeficiency virus-negative patient after kidney transplantation without primary skin involvement.

Mean Platelet Volume Has Prognostic Value in Chronic Lymphocytic Leukemia.

PURPOSE: Mean platelet volume (MPV) is a readily accessible and commonly tested hematological indicator. Recent studies revealed a significant impact of MPV on the course and prognosis of many diseases, including some types of cancer, as well as on the incidence of atrial fibrillation and bleeding. The study aimed to perform a retrospective analysis of MPV in terms of time to first treatment (TTFT) and to determine its prognostic value in the group of patients with chronic lymphocytic leukemia (CLL). Moreover, the study includes a retrospective analysis of platelet parameters in patients treated with ibrutinib concerning bleeding and atrial fibrillation. PATIENTS AND METHODS: The study included 523 patients with CLL, for 344 the most important cytogenetic aberrations were reported. The Mann-Whitney, Kruskal-Wallis, Kaplan-Meier, chi-squared, log­rank tests and multivariate Cox proportional hazard regression model were used to analyze collected data. RESULTS: The receiver operating characteristic curve analysis was performed to identify optimal cut-off value for MPV. The analysis of survival curves showed that in the group of patients with higher values of MPV TTFT was significantly longer than in the group with lower MPV (17.9 vs 36 months, p=0.0015, cut-off value for MPV= 10.4 fl). In multivariate Cox proportional hazard regression model low MPV, the presence of del11q and del13q provided independent prognostic value for TTFT (HR=0.69, 95%-CI, 0.5293 to 0.9081; p=0.0078; HR=1.76, 95%-CI, 1.3000 to 2.3882, p=0.0003, HR=0.74, 95%-Cl, 0.5674 to 0.9588, p=0.0229, respectively). In the group treated with ibrutinib, 59 patients had no significant correlation between MPV level and the incidence of therapy complications, although in the group of patients with low MPV there was a tendency for more frequent occurrence of atrial fibrillation (p=0.259). CONCLUSION: Low MPV values are associated with unfavorable prognosis and might represent a novel, independent prognostic factor in CLL.

Oncologist Burnout Syndrome in Eastern Europe: Results of the Multinational Survey.

PURPOSE: Burnout is defined as a three-dimensional syndrome-emotional exhaustion (EE), depersonalization (DP), and reduced personal accomplishment (PA)-caused by chronic occupational stress. The aim of the current study was to investigate the prevalence of burnout among oncologists in Eastern Europe and to identify the contributing factors. METHODS: The study was conducted as an online survey between October 2017 and March 2018. Oncologists (including medical, radiation, clinical, and surgical oncologists) from 19 countries were invited to participate. The survey consisted of 30 questions, including the standardized burnout instrument, Maslach Burnout Inventory, and eight demographic questions. Burnout risk was scored according to the scoring manual for health care workers. RESULTS: The study included 637 oncologists. Overall, 28% were at low or intermediate risk and 72% were at high risk for burnout. Forty-four percent of participants were at high risk for EE, 28.7% for DP, and 47.3% for PA. EE risk was associated with female sex. DP risk was highest among clinical and radiation oncologists, whereas PA risk was positively correlated with years of service, percentage of cancer deaths, and availability of the number of oncologists. In multivariate logistic regression analysis, burnout was significantly associated with standardized cancer mortality and fewer years of practice. CONCLUSION: Burnout among oncologists in Eastern Europe is high, and younger oncologists are the most vulnerable group. Preventive measures should be taken to address this issue, which negatively affects optimal care delivery and poses a threat to oncologists' health and well-being.

Increased serum levels of Galectin-9 in patients with chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults. Despite improvements in treatment, CLL is still considered an incurable disease. The aim of the present study was to evaluate galectin-1, -3 and -9 (Gal-1, -3 and -9) and Gal-3 binding protein (Gal-3BP) as prognostic and predictive factors in patients with CLL. Serum concentrations of Gal-1, -3 and -9 and Gal-3BP were measured in 48 patients with CLL and 30 control patients, using multiplex bead arrays. In patients with CLL, galectin concentrations were assessed prior to, during and following treatment. In patients with CLL who were untreated, galectin concentrations were measured twice with a 6-month interval. The serum level of Gal-9 was significantly increased (P<0.0001) in patients with CLL compared with the control group, and was associated with the clinical stage according to Binet classification, as well as poor cytogenetic and serum CLL prognostic factors. In addition, patients with CLL, who exhibited treatment failure, exhibited higher concentrations of Gal-9 (P=0.06) and Gal-3BP (P=0.009) at the end of the treatment when compared with patients under complete remission or stabilization of the disease. The serum level of Gal-3 was significantly decreased (P=0.012) in patients with CLL compared with the control group. These results suggest that Gal-9 is a potential prognostic factor in patients with CLL. The predictive value of Gal-9 requires further study in larger cohorts of patients.

Efficacy and safety of the obinutuzumab-chlorambucil combination in the frontline treatment of elderly CLL patients with comorbidities - Polish Adult Leukemia Group (PALG) real-life analysis.

Introduction Fludarabine- or bendamustine­based upfront immunochemotherapy is the current standard of care in fit patients with chronic lymphocytic leukemia (CLL). These regimens are poorly tolerated by patients with comorbidities, for whom the obinutuzumab-chlorambucil combination became the recommended first­line treatment. Objectives We aimed to analyze real­life experience with the obinutuzumab-chlorambucil combination as the frontline treatment in elderly and unfit patients. Patients and methods The retrospective analysis included 86 elderly patients (median age, 74 years) with CLL and a significant burden of comorbidities, treated with obinutuzumab-chlorambucil as the frontline regimen. All patients had a Cumulative Illness Rating Scale score greater than 6 and/or creatinine clearance of 30 to 69 ml/min. Results Overall response rate at 2 months after treatment completion was 95.3%, with complete remission (CR) rate of 43% and partial remission (PR) rate of 52.3%. Stable disease rate was 4.7%. Progressive disease was not observed after treatment completion. The median progression­free survival (PFS) was not reached after a median follow­up of 18 months; estimated PFS at 30 months was 62%. We observed 6 relapses (7%), 3 (3.5%) in patients obtaining CR, and 3 (3.5%) in those with PR after immunochemotherapy. The most frequent adverse events were neutropenia and infusion­related reactions (IRRs). Grade-3 neutropenia occurred in 11.6% of patients, and grade-3 IRRs, in 2.3%. There were no adverse events of grade 4 or 5. Conclusions Our data confirm that the obinutuzumab-chlorambucil combination is an effective and well­tolerated regimen in untreated CLL patients with comorbidities.

Galectin Targeted Therapy in Oncology: Current Knowledge and Perspectives.

The incidence and mortality of cancer have increased over the past decades. Significant progress has been made in understanding the underpinnings of this disease and developing therapies. Despite this, cancer still remains a major therapeutic challenge. Current therapeutic research has targeted several aspects of the disease such as cancer development, growth, angiogenesis and metastases. Many molecular and cellular mechanisms remain unknown and current therapies have so far failed to meet their intended potential. Recent studies show that glycans, especially oligosaccharide chains, may play a role in carcinogenesis as recognition patterns for galectins. Galectins are members of the lectin family, which show high affinity for ß-galactosides. The galectin-glycan conjugate plays a fundamental role in metastasis, angiogenesis, tumor immunity, proliferation and apoptosis. Galectins' action is mediated by a structure containing at least one carbohydrate recognition domain (CRD). The potential prognostic value of galectins has been described in several neoplasms and helps clinicians predict disease outcome and determine therapeutic interventions. Currently, new therapeutic strategies involve the use of inhibitors such as competitive carbohydrates, small non-carbohydrate binding molecules and antibodies. This review outlines our current knowledge regarding the mechanism of action and potential therapy implications of galectins in cancer.

Efficacy and safety of vitamin D supplementation in patients with chronic lymphocytic leukemia.

BACKGROUND: Vitamin D (VD) deficiency in chronic lymphocytic leukemia (CLL) is associated with inferior prognosis, shorter time to treatment and worse overall survival. VD deficiency is the first potentially modifiable prognostic factor in CLL. Currently, however, there is a lack of studies concerning VD supplementation in CLL patients. AIM: To evaluate the efficacy and safety of VD supplementation in patients with CLL. METHODS: A 6-month interventional study was conducted in CLL patients with lower serum 25-OH-D3 concentrations (< 30 ng/ml) than currently recommended. Patients with VD insufficiency (20-30 ng/ml) received 2000 IU of cholecalciferol/day, patients with moderate deficiency (10-19.9 ng/ml) received 4000 IU/day, and patients with severe VD deficiency (<10 ng/ml) received 6000 IU/day. RESULTS: In the analyzed group of 13 CLL subjects, only 1 patient had a VD level within the optimal range (30-80 ng/ml), 7 had an insufficient concentration, 4 had moderate deficiency, and 1 had severe deficiency. Secondary hyperparathyroidism was diagnosed in 4 subjects. Cholecalciferol supplementation (mean dose of 3384 ± 1211 IU) was followed by a significant increase in 25-OH-D3 concentration (from 17.3 ± 5.8 to 41.4 ± 17.5 ng/ml; p<0.05) and decrease in PTH (p<0.05). Five patients did not achieve the recommended 25-OH-D3 concentration. Calcium level remained unchanged and no patients developed hypercalcemia. CONCLUSIONS: VD replenishment is safe and can be effectively achieved by means of the employed cholecalciferol dosage in the majority of patients. However, some subjects may require higher doses to obtain the optimal level and immune function.